Materials and Methods
The Leiden University Medical Center serves as the national referral center for laser treatment in TTTS pregnancies in The Netherlands since 2000. Surviving children of all TTTS pregnancies treated with fetoscopic laser surgery were routinely assessed in our long-term outcome clinic since the start of our laser program, except, for organizational reasons, in the period between 2006 and 2007. We previously reported on the neurodevelopmental outcome at 2 years of age of our first cohort, treated between 2000 and 2005. We evaluated neurodevelopmental outcome of all surviving children treated between 2008 and 2010, and compared the 2 groups.
TTTS was diagnosed by using standard prenatal ultrasound criteria and staged according to standard criteria. All fetoscopic laser procedures were performed by the same group of experienced operators during both study periods. Details on the laser technique used at our center and the short-term outcome results have previously been reported. During the second study period, the majority of TTTS cases were also included in a randomized controlled trial, the Solomon study (NTR1245) comparing laser coagulation of the entire vascular equator, the Solomon technique, with the standard selective laser technique.
The following antenatal and neonatal data were recorded: gestational age at the time of laser treatment, stage of TTTS, occurrence of twin anemia-polycythemia sequence (TAPS) or recurrence of TTTS after laser, fetal demise, gestational age at delivery, birthweight, severe cerebral injury and neonatal death. TAPS was diagnosed according to antenatal and/or postnatal criteria. Severe cerebral injury was defined as intraventricular hemorrhage ≥ grade III, cystic periventricular leukomalacia ≥ grade II, ventricular dilatation ≥97th percentile, porencephalic cysts, arterial, or venous infarction detected on cerebral imaging. Socioeconomic status of the parents was registered as high, average, or low according to the Dutch Sociaal en Cultureel Planbureau. The follow-up visit was assessed at age 2 years (corrected for prematurity) and included a physical and neurologic examination and an assessment of cognitive and motor development using the Dutch version of the Bayley Scales of Infant and Toddler Development second edition (BSID-II) in the old cohort and third edition (BSID-III) in the new cohort by certified examiners. Both tests (BSID-II and BSID-III) provide a cognitive development and motor development score that follow a normal distribution with a mean of 100 and a standard deviation (SD) of 15. When each separate score was below 70, which is >2 SD below the mean, this was indicative of a severe delay in either cognitive or motor development. A score below 85, >1 SD below the mean, was indicative of at least mild to moderate delay. Cerebral palsy (CP) was defined according to the European CP Network and classified as diplegia, hemiplegia, quadriplegia, dyskinetic, or mixed. A composite outcome, termed neurodevelopmental impairment (NDI), was defined as any of the following: CP, cognitive development score of less than 70, motor development score of less than 70, bilateral blindness, or bilateral deafness requiring amplification.
The primary aim of our study was to compare the incidence of NDI between both cohorts. The secondary aim was to determine risk factors associated with NDI. The institutional review board of the Leiden University Medical Center approved the study and all parents gave written informed consent for their children.
Statistics
Data are reported as means with SD or as medians with interquartile range, as appropriate. Statistical analysis was performed using the t test and Mann-Whitney test for continuous variables. The χ 2 test and Fisher exact test were used for categorical variables, as appropriate. Analysis for risk factors possibly contributing to the neurodevelopmental impairment was conducted using univariate and multivariate regression methods. The following potential risk factors for neurodevelopmental impairment were studied in a univariate logistic regression model: gestational age at laser surgery, Quintero stage, fetal demise of 1 twin, gestational age at delivery, birthweight, treatment failure defined as postlaser TAPS or recurrent TTTS, and severe cerebral injury. The multivariate logistic regression model included all variables that showed significant association in the univariate analysis. Results are expressed as odds ratio (OR) with 95% confidence interval (CI). All analyses were conducted using the generalized estimated equation module to account for the effect that observations within twins are not independent. A P value of less than .05 was considered significant. Statistical analysis was executed with computer software (SPSS 20.0, SPSS, Inc., Chicago, IL).
Results
During the first study period between 2000 and 2005, 113 TTTS pregnancies were treated with fetoscopic laser surgery. During the second study period, between 2008 and 2010, we treated 106 TTTS pregnancies. The incidence of intrauterine fetal demise was 26% (58/226) and 16% (33/212), respectively ( P = .01) with significant more double fetal demises in the first cohort (17% vs 7%; P < .01). Although in both groups the majority of pregnancies were classified as Quintero stage II or III, the recent cohort comprised significantly more stage III diagnoses at therapy ( P = .02). Median gestational age at birth and median birthweight in live-born neonates was higher in the first cohort, 34 vs 32 weeks ( P < .01) and 1982.5 vs 1700 g ( P < .01), respectively.
Severe cerebral injury was detected in 10% (16/168) of live-born neonates in the first cohort and 6% (11/179) in the recent cohort ( P = .32). Neonatal death rate was similar, 6% (10/168) and 5% (9/179), respectively ( P = .90). Overall survival to 30 days was significantly higher in the recent cohort, 70% (158/226) vs 80% (170/212), respectively ( P = .01). Baseline characteristics of the entire cohort are presented in Table 1 .
| Characteristic | Cohort 2000-2005, n = 113 pregnancies | Cohort 2008-2010, n = 106 pregnancies | P value |
|---|---|---|---|
| SES | |||
| Low | 32/113 (28) | 27/106 (25) | .65 |
| Intermediate | 55/113 (49) | 44/106 (41) | .34 |
| High | 26/113 (23) | 35/106 (33) | .31 |
| Gestational age at laser, wks | 20.1 ± 3.1 | 20.1 ± 3.3 | .93 |
| Quintero stage, n (%) | 2 (1) | 3 (1) | .35 |
| I | 11 (10) | 14 (13) | .53 |
| II | 49 (43) | 30 (28) | .02 |
| III | 46 (41) | 61 (58) | .02 |
| IV | 7 (6) | 1 (1) | .07 |
| Fetal demise | 58/113 (26) | 33/106 (16) | .01 |
| Single | 20/113 (9) | 19/106 (9) | > .99 |
| Double | 38/113 (17) | 14/106 (7) | < .01 |
| TAPS or recurrent TTTS | 15/113 (13) | 16/106 (15) | .59 |
| TAPS | 9/113 (8) | 15/106 (14) | .04 |
| Recurrent TTTS | 6/113 (5) | 1/106 (1) | .02 |
| Gestational age at birth, wks | 34 (5) | 32 (6) | < .01 |
| Birthweight, g | 1982.5 (1258) | 1700 (870) | < .01 |
| Severe cerebral injury | 16/168 (10) | 11/179 (6) | .32 |
| Neonatal death | 10/168 (6) | 9/179 (5) | .90 |
| Overall perinatal survival | 158/226 (70) | 170/212 (80) | .01 |
In both cohorts, follow-up data were obtained from 97% (153/158 and 165/170) of surviving children. Seven children could not be assessed because the parents declined consent. Contact information was lost for 2 children. One child was excluded from the analysis because of infantile Tay-Sachs disease; the cotwin was a fetal demise.
All children underwent physical and neurologic examination but 3 children did not complete the motor scale of the BSID-III and 8 children did not complete the cognitive and motor scale. No significant differences in antenatal and neonatal characteristics and socioeconomic status were found between the included and lost-to-follow-up group. A flow chart showing the derivation of the study population is shown in the Figure . Baseline characteristics of the TTTS survivors included for follow-up are presented in Table 2 .
| Characteristic | Cohort 2000-2005, n = 153 children | Cohort 2008-2010, n = 165 children | P value |
|---|---|---|---|
| SES | |||
| Low | 35 (23) | 49 (30) | .52 |
| Intermediate | 76 (50) | 76 (46) | .58 |
| High | 42 (27) | 40 (24) | .20 |
| Donor | 79 (52) | 84 (51) | .88 |
| Gestational age at laser, wks | 20.4 ± 3.4 (15–28) | 20.4 ± 3.4 (14–29) | .86 |
| Quintero stage, median (range) | 2 (1) | 3 (1) | .07 |
| I, n (%) | 19 (12) | 22 (13) | .87 |
| II, n (%) | 69 (45) | 45 (27) | < .01 |
| III, n (%) | 59 (39) | 95 (58) | < .01 |
| IV, n (%) | 7 (5) | 2 (1) | .09 |
| Fetal demise cotwin | 19 (12) | 17 (10) | .60 |
| Gestational age at birth, wks | 34 (5) | 33 (6) | < .01 |
| 37-40 | 37 (24) | 15 (9) | < .01 |
| 32-36 | 70 (46) | 82 (50) | .50 |
| 24-31 | 46 (30) | 68 (41) | .05 |
| Birthweight, g | 2000 (1202.5) | 1710 (851) | < .01 |
| Female | 79 (52) | 91 (55) | .53 |
The incidence of NDI in children with complete follow-up was 18% (28/152) in the first cohort, vs 6% (10/155) in the recent cohort ( P < .01). NDI was due to CP in 12 cases in the first compared with 5 cases in the recent cohort ( P = .07). CP was classified as quadriplegia (n = 5), diplegia (n = 2), and hemiplegia (n = 5) and as quadriplegia (n = 2) and hemiplegia (n = 3), respectively. Severe cognitive developmental delay occurred in 14 cases in the first cohort compared with 5 cases in the recent cohort ( P = .03). Severe motor development delay was detected in 20 cases in the first cohort compared with 5 cases in the recent cohort ( P < .01). Details on the combinations of abnormal findings detected in the children with NDI are presented in Table 3 . In the first cohort, 36% (10/28) of children with NDI also had severe cerebral injury, vs 60% (6/10) in the recent cohort ( P = .27). Mean BSID cognitive scores in the first cohort were 7 points lower compared with the recent cohort, 94.6 ± 17.0 vs 102.0 ± 12.3, respectively ( P < .01). Mean BSID motor scores in the first cohort were 12 points lower, 89.7 ± 17.7 vs 101.8 ± 13.8, respectively ( P < .01).
| Variable | 2000-2005, n = 153 | 2008-2010, n = 165 |
|---|---|---|
| CP | 1 (1) | 2 (1) |
| Cognitive development <2 SD | 6 (4) | 3 (2) |
| Motor development <2 SD | 6 (4) | 1 (1) |
| CP and cognitive and motor development <2 SD | 4 (3) | 1 (1) |
| CP and cognitive development <2 SD | 1 (1) | 0 |
| CP and motor development <2 SD | 5 (3) | 2 (1) |
| CP and bilateral deafness | 1 (1) | 0 |
| Cognitive and motor development <2 SD | 3 (2) | 1 (1) |
| Cognitive and motor development <2 SD and deafness | 1 (1) | 0 |
| Neurodevelopmental impairment a | 28 (18) | 10 (6) |
a Neurodevelopmental impairment included any of the following: cerebral palsy, cognitive development <2 SD, motor development <2 SD, bilateral deafness, or blindness.
Univariate analysis of potential risk factors for NDI was performed for both cohorts ( Table 4 ). Risk factors found to be associated with NDI were advanced gestational age at laser surgery (OR, 1.12 for each week; 95% CI, 1.01–1.25; P = .03), lower birthweight (OR, 1.08 for each 100 g decrease; 95% CI, 1.01–1.15; P = .02), and severe cerebral injury at birth (OR, 40.00; 96% CI, 13.39–119.46; P < .01). We found a (small) positive correlation between gestational age at laser and Quintero stage (r = 0.11; P = .05) and a strong positive correlation between gestational age at birth and birthweight (r = 0.85; P < .01).
| Characteristics | NDI, (n = 38/318) | No NDI, (n = 280/318) | P value | Univariate OR (95% CI) | P value | Multivariate OR (95% CI) |
|---|---|---|---|---|---|---|
| Gestational age at laser, wks a | 21.6 ± 3.9 | 20.2 ± 3.3 | .03 | 1.12 (1.01–1.25) | .07 | 1.10 (0.99–1.23) |
| Birthweight, g b | 1505 (937) | 1893 (990) | .02 | 1.08 (1.01–1.15) | .47 | 1.03 (0.95–1.10) |
| Severe cerebral injury, yes | 16/21 (76) | 5/21 (24) | < .01 | 40.00 (13.39–119.46) | < .01 | 34.86 (11.83–102.75) |
| Severe cerebral injury, no | 22/297 (7) | 275/297 (93) | — | — | — | — |
| SES | ||||||
| Low | 8/82 (10) | 74/82 (90) | .14 | 2.01 (0.80–5.04) | ||
| Intermediate | 15/152 (10) | 137/152 (90) | — | — | ||
| High | 15/84 (18) | 69/84 (82) | — | — | ||
| Quintero stage | ||||||
| I | 1/41 (2) | 40/41 (98) | .06 | 0.09 (0.01–1.10) | ||
| II | 12/114 (11) | 102/114 (89) | — | — | ||
| III | 23/154 (15) | 131/154 (85) | — | — | ||
| IV | 2/9 (22) | 7/9 (78) | — | — | ||
| FD of cotwin, yes | 3/36 | 33/36 | .48 | 1.56 (0.45–5.35) | ||
| FD of cotwin, no | 35/282 | 247/282 | ||||
| TAPS or recurrent TTTS, yes | 3/47 (6) | 44/47 (94) | .21 | 0.46 (0.14–1.56) | ||
| TAPS or recurrent TTTS, no | 35/271 (13) | 236/271 (87) | — | — | ||
| Gestational age at birth, wks c | 31 (5) | 33 (6) | .12 | 0.93 (0.85–1.02) |
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